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Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence.

  • Vizioli, Maria Grazia1, 2, 3, 4, 5
  • Liu, Tianhui6
  • Miller, Karl N6
  • Robertson, Neil A1, 2
  • Gilroy, Kathryn1, 2
  • Lagnado, Anthony B7, 8
  • Perez-Garcia, Arantxa1, 2
  • Kiourtis, Christos1, 2
  • Dasgupta, Nirmalya6
  • Lei, Xue6
  • Kruger, Patrick J7
  • Nixon, Colin1
  • Clark, William1
  • Jurk, Diana7, 8
  • Bird, Thomas G1, 9
  • Passos, João F7, 8
  • Berger, Shelley L10
  • Dou, Zhixun3, 4, 5
  • Adams, Peter D1, 2, 6
  • 1 Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom. , (United Kingdom)
  • 2 Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom. , (United Kingdom)
  • 3 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  • 4 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
  • 5 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
  • 6 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
  • 7 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA.
  • 8 Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom. , (United Kingdom)
  • 9 MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH1 64TJ, United Kingdom. , (United Kingdom)
  • 10 Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Published Article
Genes & development
Publication Date
Mar 01, 2020
DOI: 10.1101/gad.331272.119
PMID: 32001510


Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS-STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS-JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP. © 2020 Vizioli et al.; Published by Cold Spring Harbor Laboratory Press.

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